Nucleolar repression facilitates initiation and maintenance of senescence

Abstract

Tumor cells with defective apoptosis pathways often respond to chemotherapy by entering irreversible cell cycle arrest with features of senescence. However, rare cells can bypass entry to senescence, or re-enter cell cycle from a senescent state. Deficiency in senescence induction and maintenance may contribute to treatment resistance and early relapse after therapy. Senescence involves epigenetic silencing of cell cycle genes and reduced rRNA transcription. We found that senescence-inducing treatments such as DNA damage and RNA polymerase I inhibition stimulate the binding between the nucleolar protein NML (nucleomethylin) and SirT1. The NML complex promotes rDNA heterochromatin formation and represses rRNA transcription. Depletion of NML reduced the levels of H3K9Me3 and H3K27Me3 heterochromatin markers on rDNA and E2F1 target promoters in senescent cells, increased rRNA transcription, and increased the frequency of cell cycle re-entry. Depletion of the nucleolar transcription repressor factor TIP5 also promoted escape from senescence. Furthermore, tumor tissue staining showed that breast tumors without detectable nucleolar NML expression had poor survival. The results suggest that efficient regulation of nucleolar rDNA transcription facilitates the maintenance of irreversible cell cycle arrest in senescent cells. Deficiency in nucleolar transcription repression may accelerate tumor relapse after chemotherapy.

Inhibition of nucleolar stress response by Sirt1: A potential mechanism of acetylation‐independent regulation of p53 accumulation

“…Supporting our current results, several recent studies have also pointed to a crucial role of Sirt1 in orchestrating nucleolar events (Voit, Seiler, & Grummt, ). In particular, it has been shown that Sirt1 can interact (maybe indirectly) with another nucleolar protein, nucleomethylin, and formation of this protein complex is involved in modulating ribosomal biogenesis and cellular senescence in response to changes in energy supply (Murayama et al, ; Yang et al, ; Yang, Song, Chen, Soliman, & Chen, ). To our knowledge, our study is the first which reports that Sirt1 is implicated in regulating NSR.…”

Nucleolus association of chromosomal domains is largely maintained in cellular senescence despite massive nuclear reorganisation

“…Remarkably, we found also BAZ2A(TIP5) among the handful of chromatin regulator genes that show elevated expression level in senescence. The Tip5 protein is thought to be involved in silencing and constitutive heterochromatin formation at rDNA, centromeres and telomeres (Guetg et al 2010;Postepska-Igielska et al 2013), and it has been recently reported that depletion of Tip5 promotes escape from senescence (Yang et al 2015b). This suggests a role for Tip5 in the regulation of a subset of H3K9me3-marked chromatin domains in senescence.…”

Estrogen Signaling Induces Mitochondrial Dysfunction-Associated Autophagy and Senescence in Breast Cancer Cells

“…Consistent with this observation is the fact that MDA-MB-231 cells have significant proliferative and metastatic potential [65], poor responsiveness to anti-growth chemotherapy [66] and reduced susceptibility to autophagy [67]. Moreover, reversal of senescence occurs more often in cells like MDA-MB-231 as they are incapable of repressing rRNA transcription [68] due to reduced expression of the JmjC domain-containing histone demethylase 1B (JHDM1B) [69].…”